For those who experience it, as well as for their families, communities and employers, pain is more than a minor inconveniencexe2x80x94it is a serious physical, emotional, social and economic burden. Because more than two million people in the United States alone are incapacitated by chronic pain on any given day (T. M. Jessell and D. D. Kelly, Pain and Analgesia in PRINCIPLES OF NEURAL SCIENCE, 3rd edition (E. R. Kandel, J. H. Schwartz, T. M. Jessell, ed., 1991)), the number of people and entities bearing these burdens is quite large.
Unfortunately, current treatments for pain are only partially effective, and many also cause debilitating or dangerous side effects. For example, non-steroidal anti-inflammatory drugs (xe2x80x9cNSAIDsxe2x80x9d) such as aspirin, ibuprofen and indomethacin are moderately effective against inflammatory pain but they are also renal toxins, and high doses tend to cause gastrointestinal irritation, ulceration, bleeding and confusion. Patients treated with opioids frequently experience confusion, and long-term opioid use is associated with tolerance and dependence. Local anesthetics such as lidocaine and mixelitine simultaneously inhibit pain and cause loss of normal sensation. Thus, there is a need for safe and effective treatments for pain.
Enhanced understanding of the molecular basis of pain should aid the development of pain medications. Pain is a particularly challenging subject because it is a perception based on signals received from the environment and transmitted and interpreted by the nervous system. Noxious stimuli such as heat and touch cause specialized sensory receptors in the skin to send signals to the central nervous system (xe2x80x9cCNSxe2x80x9d). This process is called nociception, and the peripheral sensory neurons that mediate it are nociceptors. Depending on the strength of the signal from the nociceptor(s) and the abstraction and elaboration of that signal by the CNS, a person may or may not experience a noxious stimulus as painful.
While pain is not enjoyable, it is crucialxe2x80x94without it, we would be oblivious to many environmental dangers. When our perception of pain is properly calibrated to the intensity of the stimulus, pain serves its intended protective function. However, certain types of tissue damage cause a phenomenon, known as hyperalgesia or pronociception, in which relatively innocuous stimuli are perceived as intensely painful because the person""s pain thresholds have been lowered. Both inflammation and nerve damage can induce hyperalgesia. Thus, persons afflicted with inflammatory conditions, such as sunburn, osteoarthritis, colitis, carditis, dermatitis, myositis, neuritis, collagen vascular diseases (which include rheumatoid arthritis and lupus) and the like, often experience enhanced sensations of pain. Similarly, trauma, surgery, amputation, abscess, causalgia, collagen vascular diseases, demyelinating diseases, trigeminal neuralgia, cancer, chronic alcoholism, stroke, thalamic pain syndrome, diabetes, herpes infections, acquired immune deficiency syndrome (xe2x80x9cAIDSxe2x80x9d), toxins and chemotherapy cause nerve injuries that result in excessive pain. Apparently, the reduced pain thresholds characteristic of hyperalgesia are due to alterations in the way that nociceptors adjacent to the inflammation or damaged nerves respond to noxious stimuli. If the mechanisms by which nociceptors transduce external signals under normal and hyperalgesic conditions were better understood, it might be possible to identify processes unique to hyperalgesia that, when interrupted, could inhibit the lowering of the pain threshold and thereby lessen the amount of pain experienced. Since such a treatment for chronic pain would act at the level of the sensory afferent neurons, it would bypass the problems associated with drugs that act on the CNS. If the treatment incapacitated a transduction pathway specific to nociceptors and/or not involved in mediating other signals, then the potential for treatment-induced side effects would be small. The present invention provides such a method of alleviating pain.
The present invention is a method of lessening pain comprising administering to a subject in need thereof, an effective amount of an inhibitor of the s isozyme of protein kinase C (xe2x80x9cPKCxcex5xe2x80x9d). A second aspect of the invention is the use of a PKCxcex5 inhibitor to decrease hyperalgesia, preferably without impairing nociception. Inhibitors that are selective for PKCxcex5 are preferred, and local administration of the inhibitor is preferred. A third aspect of the invention is a method of identifying compounds that modulate pain comprising selecting a test compound that modulates the activity of PKCxcex5 and administering said test compound to a subject to determine whether pain is modulated. A fourth aspect of the invention is a pharmaceutical composition comprising an inhibitor of PKCxcex5 and an analgesic agent that is not an inhibitor of PKCxcex5. This invention is well suited to the treatment of subjects having acute or chronic pain caused by neuropathic or inflammatory conditions.